Baseline and longitudinal ctDNA biomarkers in GEICAM/2013-02 (PEARL) trial cohort 2 comparing palbociclib and fulvestrant (PAL + FUL) versus capecitabine (CAPE).
Authors: Javier Pascual, Miguel Martin, Paula Proszek, Miguel Gil-Gil, Alistair Reay, Christoph Zielinski, Jesus Herranz, Ros Cutts, Manuel Ruiz-Borrego, Andrew Feber, Eva M. Ciruelos, Claire Swift, Montserrat Muñoz, Begona Bermejo, Mireia Margelí, Yuan Liu, Isaac Garcia-Murillas, Michael Hubank, Nicholas C. Turner
Journal: Journal of Clinical Oncology (2022)

1019 Background: The randomized PEARL trial found no superiority of PAL plus endocrine therapy over CAPE in patients (pts) with metastatic HR-positive, HER2-negative breast cancer resistant to aromatase inhibitors (Martin M, Ann Oncol 2020). We investigated associations between baseline genomic landscape and on-treatment plasma ctDNA dynamics with progression free survival, in pts from cohort 2 of the trial. Methods: Plasma was collected for ctDNA analysis from -7 days to cycle 1-day 1 (C1D1) for baseline prognostic analysis and cycle 1-day 15 (C1D15) when available, and sequenced with an in-house error-corrected targeted capture panel encompassing 21 genes commonly altered in breast cancer. For predictive ctDNA dynamics analysis, a pre-specified criteria of 14 minimum days of treatment in first cycle was required and variants with VAF &lt;0.5% in C1D1, set as limit of detection, were excluded. The circulating DNA ratio (CDR) was calculated as a weighted mean for potentially clonal mutations at C1D1. The optimal cut-off for predicting PFS was assessed by fitting a range of cut-offs, identifying the one with lower p-value on the log-rank test. Adjusted p-values, potential overestimation corrected by a shrinkage factor and bootstrapping techniques to calculate the CI95% were used in the cutpoint Cox regression model. Results: A total of 201 pts had a C1D1 sample sequenced for baseline prognostic analysis, 146 (73%) had baseline mutations identified and 55 (27%) had no mutations. 187 (93%) pts had a paired C1D15 sample for CDR calculations. Of these, 134 (72%) had baseline mutations detected, 120 of them (90%) above 0.5%, 14 (10%) had no calls, 1 pair failed sequencing. Both baseline and CDR subsets were representative of the overall study population. Pts with TP53 mutations had worse PFS in the overall population (4.4 vs 9.3 months, logrank p= 0.04), with no differences between treatments. For on-treatment ctDNA dynamic analysis, median CDR (suppression) was lower in the CAPE arm (0.07 vs 0.21, p&lt;0.01). There was an association between optimal cut-offs predicting PFS both in CAPE (suppressed 16.6 months vs high ctDNA 4.2 months, HR 2.37, CI95% 0.96-5.83, p=0.05) and PAL + FUL arms (suppressed 15.7 months vs high ctDNA 5.5 months, HR 2.14, CI95% 0.92-5, p=0.06). More ctDNA suppression associated with likelihood of objective responses (median CDR 0.1 in objective responders vs median CDR 0.2 in progressive disease p=0.03), with no statistical significance when stratified per treatment. Conclusions: In PEARL cohort 2, TP53 mutations associated with poor outcome regardless of treatment allocation, suggesting aggressive behaviour not specifically linked to endocrine resistance. Lack of ctDNA suppression associated with worse outcome in both patient groups. Capecitabine resulted in greater ctDNA suppression at C1D15, likely reflecting faster ctDNA suppression.